1. Field of the Invention
The invention generally relates to new anti-cancer compounds, acting through a new mechanism of action by simultaneous inhibition of leukemia inhibitory factor (LIF) and MDM2.
2. Description of the Relevant Art
Cancer is a group of diseases characterized by the uncontrolled growth and spread of abnormal cells. If the spread is not controlled, it can result in death. Cancer may affect people at all ages, but risk for the more common varieties tends to increase with age. Cancer is caused by external factors, such as tobacco, infectious organisms, and an unhealthy diet, and internal factors, such as inherited genetic mutations, hormones, and immune conditions. These factors may act together or in sequence to cause cancer. Treatments include surgery, radiation, chemotherapy, hormone therapy, immune therapy, and targeted therapy (drugs that specifically interfere with cancer cell growth). According to American Cancer Society, about 1,685,210 new cancer cases are expected to be diagnosed in 2016 and about 595,690 Americans are expected to die of cancer in 2016, which translates to about 1,630 people per day (Cancer Facts and Figures, 2016).
Conventional cancer diagnosis and therapies to date have attempted to selectively detect and eliminate cancer cells that are largely fast-growing. Standard oncology regimens have often been largely designed to administer the highest dose of irradiation or a chemotherapeutic agent without undue toxicity, i.e., often referred to as the “maximum tolerated dose” (MTD) or “no observed adverse effect level” (NOAEL). Chemotherapeutic strategies often involve administration of a combination of chemotherapeutic agents in order to increase the efficacy of treatment. Despite the availability of a large variety of chemotherapeutic agents, these therapies have many drawbacks includes bone marrow depression, immunosuppression, gastrointestinal distress, etc.
Other novel therapeutic approaches seek to utilize targeted therapies with increased selectivity and efficacy in preselected patient populations. A recent molecularly targeted therapy is established by inhibiting the enzyme poly (ADP-ribose) polymerase (PARP) by small molecule inhibitors such as Olaparib on tumors that have a defect in the homologous DNA recombination due to BRCA mutations.
Cancer stem cells have been identified in a large variety of cancer types. Many different cancers including breast, prostate ling, pancreas etc. have showed the presence of stem cell populations that are resistant to conventional chemotherapies. Therapies that could target cancer stem cells could be of great therapeutic potential in hormone/chemotherapy refractory cancers.
Leukemia inhibitory factor, or LIF, is an interleukin 6 class cytokine that affects cell growth by inhibiting cell differentiation. LIF binds to the specific LIF receptor (LIFR-α) which forms a heterodimer with a specific subunit common to all members of that family of receptors, the GP130 signal transducing subunit. This leads to activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen activated protein kinase) cascades. LIF promotes STAT3 phosphorylation.
LIF promotes tumorigenesis in many solid tumors and mediates pro-invasive activation of stromal fibroblasts in cancer. LIF mediates TGF beta dependent actinomycin contractility, extracellular matrix remodeling leading to cancer cell invasion in fibroblasts. It is established that paracrine molecules such as TGF-beta, growth factors, and proinflammatory molecules (such as the IL-6 family of cytokines that includes LIF) are secreted by cancer cells and promote tumorigenesis. TGF-beta-mediated phosphorylation of Smad3 potentiates transcriptional regulation of many genes that assist in the proliferation of cancer cells. The role of TGF-beta/SMAD and JAK/STAT3 in signaling in tumor cell dependent proinvasive fibroblast activation and expression of alpha-smooth muscle actin (α-SMA) producing carcinoma associated fibroblast (CAF) hallmark is well known.
Leukemia Inhibitory Factor (LIF) is, thus important in sustaining pluripotency and stemcellness and embryogenesis. A critical point during mammalian pregnancy is the implantation of the blastocyst when the embryo attaches to the wall of the uterus. Females lacking a functional LIF gene are fertile, but their blastocysts fail to implant and do not develop. LIF may also be critical to endometrial receptivity in humans, as well as a wide range of other mammals, with reduced LIF expression being linked to several cases of female infertility.
LIF induces many genes that over express in cancer. One gene LIF induces over expression for is breast cancer antiestrogen resistance protein (p13Cas/BCAR1). Overexpression of p130Cas/BCAR1 has been detected in human breast cancer, prostate cancer, ovarian cancer, lung cancer, colorectal cancer, hepatocellular carcinoma, glioma, melanoma, anaplastic large cell lymphoma and chronic myelogenous leukemia. The presence of aberrant levels of hyperphosphorylated p130Cas/BCAR1 strongly promotes cell proliferation, migration, invasion, survival, angiogenesis and drug resistance.
Carcinoma-associated fibroblasts (CAF) are the most abundant population of non-cancer cells found in tumors, and their presence is often associated with poor clinical prognosis. LIF drives cancer cell-dependent pro-invasive extracellular matrix remodeling in carcinoma associated fibroblasts. It has been established that under the influence of bioactive molecules, such as LIF, within the tumor stroma, resident fibroblast are activated and promote tumorigenesis.
LIF is an important negative regulator of tumor suppressor gene p53. Down regulation of p53 by LIF is mediated by the activation of STAT3, which transcriptionally induces inhibitor of DNA binding 1 (ID1). ID1 upregulates MDM2, a natural negative regulator of p53 and promotes p53 degradation. EC330 was found to indirectly diminish the phosphorylation of SMAD thorough blocking TGF-beta. Overexpression of LIF is associated with poor prognosis and increase incidence of chemoresistance. Targeting LIF and MDM2 to reactivate p53 is a potential therapeutic strategy for chemotherapy as well as in combination with other agents to alleviate chemoresistance.
There have been few discoveries made in the field of LIF regarding the inhibition of LIF in medicine. Monoclonal antibodies against LIF have been described. For example, U.S. Pat. No. 6,156,729 claimed the use of leukemia inhibitory factor (LIF) antagonists to prevent or lessen hypertrophy.
EP Patent Application No. EP2371860 A1 claimed that LIF specific monoclonal antibody could be useful for the treatment for proliferative diseases such as cancer.
U.S. Pat. No. 9,194,872 B2 and U.S. Published Patent Application No. 2015/0133376 A1 taught the use of a leukemia inhibitory factor receptor inhibitor for the potentiation of cancer radiotherapy. U.S. Pat. No. 9,194,872 also claimed rapamycin and substituted quinoline as cancer therapy sensitizers that modulate LIF.
A receptor protein (DNA encoding fusion receptor) comprising a gp130 polypeptide linked to a single-chain leukemia inhibitory factor receptor (LIF-R) polypeptide is capable of binding both oncostatin M and leukemia inhibitory factor (LIF) has reported in U.S. Pat. No. 5,426,048.
A method for treating a mammal experiencing heart failure to prevent or lessen cardiac hypertrophy comprising administering therapeutically effective amount of LIF antagonist (antibody) and an endothelin antagonist to a mammal in need of such treatment was described in U.S. Pat. No. 6,156,733, 5,573,762 and U.S. Pat. No. 5,837,241.
The use of recombinant LIF from mammalian species to enhance implantation and development of embryos was described in U.S. Pat. No. 5,962,321.
In summary, all prior art among the area of LIF and LIFR targeting agents only included monoclonal antibodies (mAbs) and glycosylated or non-glycosylated antibody fragments. Some of these agents are in clinical trials and none has been approved to use in patients yet. Generally mAbs are expensive to produce and recognize only specific epitope(s) on an antigen. This drawback could lead to miss some variants. Moreover limited clones are available. It is therefore desirable to develop compounds that are small molecule inhibitors of LIF/LIFR and have targeted therapeutic advantage in treating cancers.